Because there is no chemotherapeutic agent which is significantly effective in prolonging the survival of patients with intracranial tumors, there has been general disillusionment with this form of therapy for brain tumors. Generally, there has been a failure to consider the multiple factors influencing the outcome of chemotherapy of brain tumors, including route of drug administration, protein binding, blood flow, vascular permeability, drug distribution to the tumor micro- environment, molecular properties of the drug, uptake of drugs by the tumor cells, tumor cell sensitivity to the drug, tumor cell kinetics and the brain reaction to the tumor and drug. In the following experiments the influence of some of these factors on the outcome of the therapy of a model brain tumor will be explored. Studies on the pathogenesis of the brain tumor after chemotherapy will be undertaken to elucidate the effects on the tumor and the reaction of the brain to the therapy. The cell kinetics of the tumor will be extensively investigated to provide a logical basis for the chemotherapy of the tumor. A combination of effective chemotherapeutic agents will be used in an effort to further increase the survival of animals bearing the intracranial tumor. Combinations of non cycle active agents with cycle active agents and mitotic inhibitors will be investigated to provide the maximum survival and facilitate the clinical evaluation of such combinations. The sensitivity of the tumor itself to the various agents without the influence of the surrounding brain and skull environments will be studied with tumors grown in the subcutaneous tissue. Finally, an evaluation of the uptake of water and lipid soluble standard drug molecules in the tumor and their distribution throughout the tumor after a single dosage will be studied to elucidate the kinetic distribution of the agents throughout the tumor.